Pregnancy represents a partially immunocompromised state in which infections caused by various pathogens such as herpes simplex virus (HSV) are poorly tolerated. Aside from the direct maternal morbidity encountered, HSV infections can be transmitted to the fetus and newborn resulting in a high acute perinatal mortality and long-term neurologic sequelae in survivors. Natural killer cell cytotoxicity (NKC) and antibody- dependent cellular cytotoxicity (ADCC) are primary immunodefense systems which are thought to play a pivotal role in HSV infection. The specific aims of this project set out to define and characterize these immune responses in pregnancy. Using an in vitro effector/target cell model, pregnant women's mononuclear effector cells will be serially tested for NKC and ADCC activity throughout gestation, specifically against HSV- infected Chang liver target cells. Based on the applicant's preliminary data which suggests an NKC deficient state in pregnancy, a single cell agarose assay will be used to further define this deficit in terms of its more basic functional components, i.e., cellular adhesion, lysis, and recycling. Known immunoregulatory agents will be tested in vitro for their ability to reconstitute this pregnancy-associated NKC deficit. Additionally, an investigation into the mechanism by which this immunoregulation occurs will be undertaken by examining cellular arachidonic acid lipoxygenation following pharmacologic reconstitution. Achievement of these objectives will improve our understanding of the immunology of HSV infection in pregnancy and provide a more rational approach to the prevention and control of this infectious and morbid process. The goals outlined to this proposal are logistically obtainable and would provide a starting point to begin my development as an independent investigator in this field of study. My recent work with Dr. Steve Kohl has provided me with a challenging research focal point and the methodology to develop it. Both my sponsors, and my department chairman, have given me clear indications of their continued support in these endeavors. This includes technical assistance, laboratory support, and adequate freedom from other clinical responsibilities. As an institution, The University of Texas Medical School is well recognized for its academic achievements further emphasizing the richness of this environment for a young investigator.